Use of derivatives of valproic acid amides and 2-valproenic acid amides for the treatment or prevention of pain and/or headache disorders

ABSTRACT

A method for the treatment or prevention of pain and/or a headache disorder using a derivative of a valproic acid amide or a 2-valproenic acid amide, as well as pharmaceutical compositions comprising these derivatives or compounds.

[0001] This application claims the benefit of U.S. ProvisionalApplication No. 60/225,973, filed Aug. 17, 2000 and U.S. ProvisionalApplication No. 60/225,977, filed Aug. 17, 2000.

[0002] Throughout this application, various references are referenced byshort citations within parenthesis. Full citations for these referencesmay be found at the end of the specification, immediately preceding theclaims. These references, in their entireties, are hereby incorporatedby reference to more fully describe the state of the art to which thisinvention pertains.

FIELD OF THE INVENTION

[0003] Disclosed is a method for the treatment or prevention of painand/or headache disorders, such as migraines, using derivatives ofvalproic acid amides and 2-valproenic acid amides.

BACKGROUND OF THE INVENTION

[0004] Pain is considered to play a basic physiological role in thedetection and localization of tissue damage or potentially damagingphysiological processes. Pain has been broadly classified assomatogenic, where a physiological explanation can be found, orpsychogenic, where the physiological explanation is not known (The MerckManual of Diagnosis and Therapy).

[0005] One example of a somatogenic pain is neuropathic pain. Generally,neuropathic pain is described as a pain which results from a dysfunctionin the central or peripheral nervous system (Tremont-Lukats, I. et al.;Woolf, C. and Mannion, R.). The pain can be both chronic and acute, andcan also be evoked by noxious stimuli, also referred to as hyperalgesia,or by non-noxious stimuli referred to as allodynia (Attal, N.).Allodynia and hyperalgesia can have mechanical causes (dynamic orstatic), or a thermal cause. Examples of neuropathic pain include: allthe painful peripheral neuropathies and specifically diabetic peripheralneuropathy; postherpetic neuralgia; and trigemincal neuralgia.Trigeminal neuralgia, for example, is the most common neuralgic syndromein the elderly. The initial drug of choice is carbamazepine. For othertypes of pain, such as postherpetic neuralgia and painful diabeticneuropathy, amitriptyline is most commonly used. Other types ofsomatogenic pain that may have neuropathic components include cancerpain, postoperative pain, low back pain, complex regional pain syndrome,phantom pain, HIV pain, arthritis (osteo-arthritis and rheumatoidarthritis) pain and migraines.

[0006] Pain may also be a symptom of headache disorders. Migrainesconstitute one of the four major categories of primary headaches(International Headache Society; Silberstein, S.D. et al.). The otherthree types of primary headaches are tension-type, cluster and amiscellaneous-type (International Headache Society; Silberstein, S.D. etal.). One current view is that there is a continuous spectrum ofheadache severity ranging from mild tension headaches to severemigraines. Others consider tension headaches and migraines to bedistinct entities.

[0007] Migraines are considered to be a familial disorder characterizedby periodic pulsatile headaches. (Principles of Neurology). Migrainesare found in about 4% of the male population and 7% of the femalepopulation. Migraines can occur in the presence or absence of an aura.An aura is a complex of focal neurological symptoms which may precede oraccompany a migraine attack (Silberstein, S. D. et al.). Auras can becharacterized by visual, sensory, or motor phenomenon, and may alsoinvolve language or brainstem disturbances (Silberstein, S. D. et al.).

[0008] A major theory regarding the pain of migraines is that it stemsfrom a form of sterile neurogenic inflammation (Moskowitz, M. A. andCutrer, F. M.). The neurogenic inflammation results in the leakage ofplasma proteins into the dura mater, which can be quantified bymeasuring the leakage of radioactive albumin (Suzzi, M. C. andMoskowitz, M. A.).

[0009] Drugs used in the treatment of headache disorders such asmigraines originate from a broad range of different drug categories.These include: 5-hydroxytryptamine agonists (5-HT₁ agonists);dihydroergotamine; ergotamine; anti-emetics; anxiolytics; non-steroidalanti-inflammatory drugs; steroids; major tranquilizers; narcotics;beta-blockers; calcium channel blockers; anti-depressants; andanti-epileptic drugs. However, not all of the drugs in these categoriesare truly effective. Considering all of the drugs which are effective,there is still a need for more efficacious drugs, as well asanti-migraine treatments with less side effects.

[0010] U.S. Pat. No. 5,585,358 describes a series of derivatives ofvalproic acid amides and 2-valproenic acid amides for the treatment ofepilepsy and other neurological disorders. However, U.S. Pat. No.5,585,358 does not teach or suggest the use of derivatives of valproicacid amides and 2-valproenic acid amides for the treatment or preventionof pain or headache disorders.

SUMMARY OF THE INVENTION

[0011] The subject invention provides a method of treating or preventingpain and/or a headache disorder in a subject comprising theadministration of a therapeutically effective amount of a derivative ofa valproic acid amide or a 2-valproenic acid amide, to thereby treat orprevent the pain and/or headache disorder. In addition, the subjectinvention contains pharmaceutical compositions comprising thesederivatives.

DESCRIPTION OF THE DRAWINGS

[0012]FIG. 1 presents the effects of the administration of VGD(valproylglycine amide or Compound 1) versus MC (methyl cellulose orvehicle) in the Chung model of neuropathic pain.

DETAILED DESCRIPTION OF THE INVENTION

[0013] The subject invention provides a method of treating subjectsuffering from pain comprising periodically administering to the subjecta therapeutically effective amount of a compound having the followingstructure:

[0014] wherein R₁, R₂, R₃ and R₄ are independently the same or differentand are hydrogen, a linear or branched C₁-C₆ alkyl group, an aralkylgroup, or an aryl group, and n is an integer which is greater than orequal to 0 and less than or equal to 3, so as to thereby treat thesubject's pain.

[0015] The subject invention also provides a method of preventing painin a subject predisposed to suffering from pain comprising periodicallyadministering to the subject a prophylactically effective dose of acompound having the following structure:

[0016] wherein R₁, R₂, R₃ and R₄ are independently the same or differentand are hydrogen, a linear or branched C₁-C₆ alkyl group, an aralkylgroup, or an aryl group, and n is an integer which is greater than orequal to 0 and less than or equal to 3, so as to thereby prevent pain inthe subject.

[0017] In addition, the subject invention provides a method of treatinga subject suffering from a headache disorder comprising periodicallyadministering to the subject a therapeutically effective dose of acompound having the following structure:

[0018] wherein R₁, R₂, R₃ and R₄ are independently the same or differentand are hydrogen, a linear or branched C₁-C₆ alkyl group, an aralkylgroup, or an aryl group, and n is an integer which is greater than orequal to 0 and less than or equal to 3, so as to thereby treat theheadache disorder.

[0019] The subject invention further provides a method of preventing aheadache disorder in a subject predisposed to suffering from a headachedisorder comprising periodically administering to the subject aprophylactically effective dose of a compound having the followingstructure:

[0020] wherein R₁, R₂, R₃ and R4 are independently the same or differentand are hydrogen, a linear or branched C₁-C₆ alkyl group, an aralkylgroup, or an aryl group, and n is an integer which is greater than orequal to 0 and less than or equal to 3, so as to thereby prevent theheadache disorder in the subject.

[0021] In one embodiment, the compound has the following structure:

[0022] In an additional embodiment, the compound isN-(2-n-propylpentanoyl)-glycinamide and has the structure:

[0023] In another embodiment, the compound isN-(2-n-propylpent-2-enoyl)-glycinamide and has the structure:

[0024] In one embodiment, the pain is acute. In another embodiment, thepain is chronic. In a further embodiment, the pain is somatogenic pain.In a preferred embodiment, the pain is neuropathic pain.

[0025] The headache disorder may be a migraine.

[0026] The headache disorder may be a cluster headache.

[0027] The headache disorder may be a tension-type headache.

[0028] The headache disorder may be a miscellaneous-type headache.

[0029] The subject may be a human being.

[0030] In one embodiment, one or more of R₁, R₂, R₃, or R₄ is a linearchain C₁-C₆ alkyl group. In another embodiment, one or more of R₁, R₂,R₃, or R₄ is a branched chain C₁-C6 alkyl group. In yet anotherembodiment, one or more of R₁, R₂, R₃, or R₄ is a benzyl, alkylbenzyl,hydroxybenzyl, alkoxycarbonylbenzyl, aryloxycarbonylbenzyl,carboxybenzyl, nitrobenzyl, cyanobenzyl, or halobenzyl group. In stillanother embodiment, one or more of R₁, R₂, R₃, or R₄ is a phenyl,naphthyl, anthracenyl, pyridinyl, indolyl, furanyl, alkylphenyl,hydroxyphenyl, alkoxycarbonylphenyl, aryloxycarbonylphenyl, nitrophenyl,cyanophenyl, halophenyl group, mercaptophenyl, or aminophenyl group.

[0031] The subject invention also provides a method of treating asubject suffering from neuropathic pain comprising administering to thesubject 500 mg of N-(2-n-propylpentanoyl)glycinamide six times per dayso as to thereby treat the subject's neuropathic pain.

[0032] In addition, the subject invention provides a method ofpreventing neuropathic pain in a subject predisposed to suffering fromneuropathic pain comprising administering to the subject 500 mg ofN-(2-n-propylpentanoyl)glycinamide six times per day so as to therebyprevent neuropathic pain in the subject.

[0033] Some of the compounds used in this invention possess chiralcenters. It is a further embodiment of this invention that thesecompounds may comprise substantially pure D or L enantiomers or racemicmixtures. It is to be understood that compounds of this invention may beof the E-(trans) or Z-(cis) geometric configuration, or a mixturethereof.

[0034] In the practice of the invention, the amount of the compoundincorporated in the pharmaceutical composition may vary widely. Factorsconsidered when determining the precise dose are well known to thoseskilled in the art. Examples of such factors include, but are notlimited to, the subject being treated and the specific pharmaceuticalcarrier, as well as the route and frequency of administration.

[0035] A therapeutically effective dose of the compound may compriseabout 10 to about 6,000 mg of the active ingredient. In one embodiment,the therapeutically effective dose comprises about 10 to about 3,000 mg.In another embodiment, the therapeutically effective dose comprisesabout 10 to about 2,000 mg. In a preferred embodiment, thetherapeutically effective dose comprises about 10 to about 1,000 mg ofthe active ingredient. In another embodiment, the therapeuticallyeffective dose comprises about 50 mg to about 500 mg. In a furtherembodiment, the therapeutically effective dose comprises about 500 toabout 4000 mg. In another embodiment, the therapeutically effective dosecomprises about 1000 to about 3000 mg. In yet another embodiment, thetherapeutically effective dose comprises about 2000 to about 3000 mg. Ina preferred embodiment, the therapeutically effective dose comprisesabout 3000 mg.

[0036] A prophylactically effective dose of the compound may compriseabout 10 to about 6,000 mg of the active ingredient. In one embodiment,the prophylactically effective dose comprises about 10 to about 3,000mg. In another embodiment, the prophylactically effective dose comprisesabout 10 to about 2,000 mg. In a preferred embodiment, theprophylactically effective dose comprises about 10 to about 1,000 mg ofthe active ingredient. In another embodiment, the prophylacticallyeffective dose comprises about 50 mg to about 500 mg. In a furtherembodiment, the prophylactically effective dose comprises about 500 toabout 4000 mg. In another embodiment, the prophylactically effectivedose comprises about 1000 to about 3000 mg. In yet another embodiment,the prophylactically effective dose comprises about 2000 to about 3000mg. In a preferred embodiment, the prophylactically effective dosecomprises about 3000 mg.

[0037] The administration of the compound may be effected once daily orup to 6 times per day. Thus, in one embodiment, the administration ofthe compound may be effected twice a day. In another embodiment, theadministration of the compound may be effected 3 times a day. In afurther embodiment, the administration of the compound may be effected 4times a day. In yet another embodiment, the administration of thecompound may be effected 5 times a day. In an added embodiment, theadministration of the compound may be effected 6 times a day.

[0038] The subject invention also provides a method of treating asubject suffering from pain comprising periodically administering to thesubject a therapeutically effective dose of composition comprising acompound having the following structure:

[0039] wherein R₁, R₂, R₃ and R₄ are independently the same or differentand are hydrogen, a linear or branched C₁-C₆ alkyl group, an aralkylgroup, or an aryl group, and n is an integer which is greater than orequal to 0 and less than or equal to 3, so as to thereby treat thesubject's pain.

[0040] Additionally, the subject invention provides a method ofpreventing pain in a subject predisposed to suffering from paincomprising periodically administering to the subject a prophylacticallyeffective dose of composition comprising a compound having the followingstructure:

[0041] wherein R₁, R₂, R₃ and R₄ are independently the same or differentand are hydrogen, a linear or branched C₁-C6 alkyl group, an aralkylgroup, or an aryl group, and n is an integer which is greater than orequal to 0 and less than or equal to 3, so as to thereby prevent pain inthe subject.

[0042] The subject invention also provides compounds containing avalproic acid moiety or a 2-valproenic acid moiety, as well aspharmaceutical compositions comprising these compounds.

[0043] The subject invention further provides a pharmaceuticalcomposition comprising the compound and a pharmaceutically acceptablecarrier. As used herein, the term “pharmaceutically acceptable carrier”encompasses any of the standard pharmaceutically accepted carriers, suchas a phosphate-buffered saline solution, water, suspen sions, powders,emulsions such as an oil/water emulsion or a triglyceride emulsion,various types of wetting agents, tablets, coated tablets, dissolvabletablets and capsules. An example of an acceptable triglyceride emulsionuseful in the intravenous and intraperitoneal administration of thecompounds is the triglyceride emulsion commercially known asIntralipid®.

[0044] Typically, pharmaceutically acceptable carriers containexcipients such as starch, milk, sugar, certain types of clay, gelatin,stearic acid, talc, vegetable fats or oils, gums, glycols, or otherknown excipients. These carriers may also include flavor and coloradditives or other ingredients.

[0045] In the practice of the invention, the administration of thepharmaceutical composition may be effected by any of the well knownmethods including, but not limited to, by inhalation, rectal, oral,intravenous, intraperitoneal, parenteral, intramuscular, transdermal,subcutaneous, sublingual, nasal, buccal, pulmonary, vaginal or topicaladministration.

[0046] Topical administration can be effected by any method commonlyknown to those skilled in the art. These methods include, but are notlimited to, incorporation of the pharmaceutical composition into creams,gels, ointments, transdermal patches or other topical formulations anddelivery systems.

[0047] When the compound is introduced orally, it may be mixed withother food forms and consumed in solid, semi-solid, suspension oremulsion form. The compound may be administered as sprinkles. In oneembodiment, the oral composition may be enterically-coated. Use ofenteric coatings are well known in the art. Commonly known entericcoatings include Eudragit S and Eudragit L (Lehman, K., 1971; Lehman, K.1973; Handbook of Pharmaceutical Excipients, 2^(nd) ed.).

[0048] The invention encompasses a pharmaceutical composition ashereinabove described wherein the carrier is a solid and the compositionis a tablet. The invention also encompasses a pharmaceutical compositionas hereinabove described wherein the carrier is a gel and thecomposition is a suppository. The invention further encompasses apharmaceutical composition as hereinabove described wherein the carrieris a liquid and the composition is a solution.

[0049] The following Experimental Details are set forth to aid in anunderstanding of the invention, and are not intended, and should not beconstrued, to limit in any way the invention set forth in the claimswhich follow thereafter.

EXPERIMENTAL DETAILS

[0050] I. Synthesis of Compounds

[0051] Compound 1 N-(2-n-propylpentanoyl)glycinamide

[0052] Compound 1 was prepared as disclosed by U.S. Pat. No. 5,585,358.

[0053] Compound 2 N-(2-n-propylpent-2-enoyl)glycinamide

[0054] Compound 2 was prepared as disclosed by U.S. Pat. No. 5,585,358.

II. EXPERIMENTAL EXAMPLES Example 1

[0055] The anti-pain effects of Compounds 1 and 2 are evaluated in amodel for traumatic nerve injury. The specific model is the ratconstriction injury model, a commonly accepted model for the evaluationof the potential of a compound to treat chronic neuropathic pain. Theend point is whether a compound can reverse cold allodynia in ratsfollowing a neuropathic injury. MC may be used as the control.

[0056] Results

[0057] Compounds 1 and 2 reverse cold allodynia in the chronicconstriction injury model of neuropathic pain with ED₅₀ values of lessthan 500 mg/kg. The effective dose is below that which has beenpreviously found to be the median ataxic dose (also referred to as theminimal neurotoxic dose). MC may be used as the control.

[0058] Discussion

[0059] The results indicate that Compounds 1 and 2 are effective for thetreatment of pain. Thus, the disclosed valproic acid amides and2-valproenic acid amides are effective for the treatment or preventionof pain, including neuropathic pain.

Example 2

[0060] The potential of Compound 1 to serve as an anti-pain agent wasstudied in the Chung model (Kim, S. H. and Chung, J. M.). This model isknown as a reliable model, predictive for human pain. (Kim, S. H. andChung, J. M.). In this model, spinal nerves L5 and L6 of the rat aretightly ligated and cut in order to induce neuropathic pain. Male Sabrarats weighing 250-275 g were used throughout the study. Underxylazine-ketamine anesthesia, both the L5 and L6 spinal nerves of oneside of the rat were tightly ligated and cut. Pain behavior was measuredfollowing operation in all groups using withdrawal latencies of the hindpaw to mechanical stimulation with von Frey filaments (tactileallodynia). The mechanical sensitivity of the foot was quantified by theoccurrence of foot withdrawal in response to normally innocuousmechanical stimuli. Eight different von Frey filaments ranging from 0.6to 26 g were used.

[0061] The efficacy (antiallodynic effect) of the compound was evaluated(300 mg/kg, per os (oral)) in eight rats at days 7 and 14 postoperationin a double-blind randomized crossover manner. The testing includedestimation of time of peak effect following drug administration andmeasurement of the ability of the compound to decrease tactileallodynia.

[0062] Results

[0063] The compound reversed tactile allodynia in the Chung model incomparison to vehicle (MC-methyl cellulose). It was found that thecompound reversed the tactile allodynia and therefore, the hind pawwithdrawal occurred at higher thresholds. The time of peak effect was 60minutes. At a statistically significant level, the compound preventedtactile allodynia when compared to vehicle 60 minutes (p=0.0207) and 120minutes (p=0.0102) following drug administration (Mann-Whitney test).The results are shown in FIG. 1.

[0064] Discussion

[0065] The results demonstrated that Compound 1 is effective for thetreatment of pain. Thus, the disclosed valproic acid amides areeffective for the treatment or prevention of pain, including neuropathicpain.

Example 3

[0066] Evaluation of the anti-headache effects of Compounds 1 and 2 arefollowed in the migraine model of Moskowitz (Suzzi, M. C. and Moskowitz,M. A.). In this model, neurogenic inflammation results in the leakage ofplasma proteins into the dura matter (plasma protein extravasation),which can be quantified by measuring the leakage of radioactive albumin(Suzzi, M. C. and Moskowitz, M. A.).

[0067] Results

[0068] The results of the experiment employing Compounds 1 and 2separately are displayed in Table 1. Individually, Compounds 1 and 2inhibit plasma protein extravasation as compared to the control group(Table 1). TABLE 1 Inhibition of Plasma Protein Extravasation byCompounds 1 and 2 Control Compound 1 Compound 2 Percent 100 <100 <100Extravasation Compared to Control

[0069] Discussion

[0070] The Moskowitz model, which is a well-accepted model of migraines(Suzzi, M. C. and Moskowitz, M. A.), shows that Compounds 1 and 2inhibit plasma protein extravasation. Thus, the disclosed valproic acidamides and 2-valproenic acid amides are effective for the treatment orprevention of headache disorders, such as migraines.

REFERENCES

[0071] U.S. Pat. No. 5,585,358, Bialer et al., issued Dec. 6, 1996.

[0072] Attal, N. 1999, Mechanism of action and rationale for use ofantiepileptic drugs in: International Congress and Symposium Series 241The Royal Society of Medicine Press Limited Ed. J M Pellock.

[0073] Handbook of Pharmaceutical Excipients, 2^(nd) ed., A. H. Kibbe,Ph.D., ed., American Pharmcaeutical Association and PharmaceuticalPress, Washington, D.C., 2000.

[0074] International Headache Society, 1988.

[0075] Kim, S. H. and Chung, J. M., 1992, Pain 50: 355-363.

[0076] Lehman, K., Acrylic Coatings in Controlled Release TabletManufacture, Manufacturing Chemist and Aerosol News, 1973, 39.

[0077] Lehman, K., Programmed Drug Release from Oral Program Forms,Pharma. Int., vol. ISS 3, 1971, 34-41.

[0078] Moskowitz, M. A. and Cutrer, F. M., Sumatriptan: areceptor-targeted treatment for migraines. Ann. Rev. Med., 1993:44:145-154.

[0079] Silberstein, S. D. et al., 1998, Headache in Clinical Practice,Pub. Isis Medical Media, Oxford.

[0080] Suzzi, M. C. and Moskowitz, M. A., The Antimigraine Drug,

[0081] Sumetriptan (GR43175), Selectively Blocks Neurogenic PlasmaExtravasation from Blood Vessels in Dura Mater, 1990, Br. J. Pharmcol.,99: 202-206.

[0082] Tremont-Lukats, I. et al., Anticonvulsants for Neuropathic Pain,Drugs, 2000, 60: 1029.

[0083] Woolf, C. and Mannion, R., Neuropathic Pain: Aetiology, Symptoms,Mechanisms and Management, Lancet, 1999, 353: 1959.

[0084] The Merck Manual of Diagnosis and Therapy, 17^(th) Ed., 1999, M.Beers and R. Berkow, eds., Merck Research Laboratories, WhitehouseStation, N.J.

[0085] Principles of Neurology, 6^(th) Ed., 1997, Adams, R. D. andVictor, M., McGraw-Hill, Inc., 148-159.

What is claimed:

1. A method of treating a subject suffering from pain comprisingperiodically administering to the subject a therapeutically effectivedose of a compound having the following structure:

wherein R₁, R₂, R₃ and R₄ are independently the same or different andare hydrogen, a linear or branched C₁-C₆ alkyl group, an aralkyl group,or an aryl group, and n is an integer which is greater than or equal to0 and less than or equal to 3, so as to thereby treat the subject'spain.
 2. The method of claim 1, wherein one or more of R₁, R₂ , R₃ or R₄is a linear chain C₁-C₆ alkyl group.
 3. The method of claim 1, whereinone or more of R₁, R₂, R₃ or R₄ is a branched chain C₁-C₆ alkyl group.4. The method of claim 1, wherein one or more of R₁, R₂, R₃ or R₄ is abenzyl, alkylbenzyl, hydroxybenzyl, alkoxycarbonylbenzyl,aryloxycarbonylbenzyl, carboxybenzyl, nitrobenzyl, cyanobenzyl, orhalobenzyl group.
 5. The method of claim 1, wherein one or more of R₁,R₂, R₃ or R₄ is a phenyl, naphthyl, anthracenyl, pyridinyl, indolyl,furanyl, alkylphenyl, hydroxyphenyl, alkoxycarbonylphenyl,aryloxycarbonylphenyl, nit:rophenyl, cyanophenyl, halophenyl group,mercaptophenyl, or aminophenyl group.
 6. The method of claim 1, whereinthe pain is acute pain.
 7. The method of claim 1, wherein the pain ischronic pain.
 8. The method of claim 1, wherein the pain is somatogenicpain.
 9. The method of claim 8, wherein the somatogenic pain isneuropathic pain.
 10. The method of claim 1, wherein the subject is a human being.
 11. The method of claim 1, wherein the administration isoral, parenteral, intraperitoneal, intravenous, intramuscular,transdermal, subcutaneous, topical or rectal administration.
 12. Themethod of claim 1, wherein the administration is by inhalation,sublingual, nasal, buccal, pulmonary or vaginal administration.
 13. Themethod of claim 1, wherein the periodic administration is effecteddaily.
 14. The method of claim 1, wherein the periodic administration iseffected less than or equal to six times a day.
 15. The method of claim14, wherein the periodic administration is effected six times a day. 16.The method of claim 1, wherein the therapeutically effective dose is anamount from about 10 mg to about 6,000 mg.
 17. The method of claim 16,wherein the therapeutically effective dose is an amount from about 500mg to about 4,000 mg.
 18. The method of claim 16, wherein thetherapeutically effective dose is an amount from about 10 mg to about3,000 mg.
 19. The method of claim 18, wherein the therapeuticallyeffective dose is about 3,000 mg.
 20. The method of claim 18, whereinthe therapeutically effective dose is an amount from about 10 mg toabout 1,000 mg.
 21. The method of claim 20, wherein the therapeuticallyeffective dose is an amount from about 50 mg to about 500 mg.
 22. Themethod of claim 1, wherein the compound has the following structure:


23. The method of claim 22, wherein the compound isN-(2-n-propylpentanoyl)glycinamide.
 24. The method of claim 23, whereinthe therapeutically effective dose is 3000 mg/day and the pain isneuropathic pain.
 25. The method of claim 22, wherein the compound isN-2(-n-propylpent-2-enoyl)glycinamide.
 26. The method of claim 22,wherein one or more of R₁, R₂, R₃ or R₄ is a linear chain C₁-C₆ alkylgroup.
 27. The method of claim 22, wherein one or more of ₁, R₂, R₃ orR₄ is a branched chain C₁-C₆ alkyl group.
 28. The method of claim 22,wherein one or more of R₁, R₂, R₃ or R₄ is aralkyl group is a benzyl,alkylbenzyl, hydroxybenzyl, alkoxycarbonylbenzyl, aryloxycarbonylbenzyl,carboxybenzyl, nitrobenzyl, cyanobenzyl, or halobenzyl group.
 29. Themethod of claim 22, wherein one or more of R₁, R₂, R₃ or R₄ is a phenyl,naphthyl, anthracenyl, pyridinyl, indolyl, furanyl, alkylphenyl,hydroxyphenyl, alkoxycarbonylphenyl, aryloxycarbonylphenyl, nitrophenyl,cyanophenyl, halophenyl group, mercaptophenyl, or aminophenyl group. 30.The method of claim 22, wherein the pain is acute pain.
 31. The methodof claim 22, wherein the pain is chronic pain.
 32. The method of claim22, wherein the pain is somatogenic pain.
 33. The method of claim 32,wherein the somatogenic pain is neuropathic pain.
 34. The method ofclaim 22, wherein the subject is a human being.
 35. The method of claim22, wherein the administration oral, parenteral, intraperitoneal,intravenous, intramuscular, transdermal, subcutaneous, topical or rectaladministration.
 36. The method of claim 22, wherein the administrationis by inhalation, sublingual, nasal, buccal, pulmonary or vaginaladministration.
 37. The method of claim 22, wherein the periodicadministration is effected daily.
 38. The method of claim 22, whereinthe periodic administration is effected less than or equal to six timesa day.
 39. The method of claim 38, wherein the periodic administrationis effected six times a day.
 40. The method of claim 22, wherein thetherapeutically effective dose is an amount from about 10 mg to about6,000 mg.
 41. The method of claim 40, wherein the therapeuticallyeffective dose is an amount from about 500 mg to about 4,000 mg.
 42. Themethod of claim 40, wherein the therapeutically effective dose is anamount from about 10 mg to about 3,000 mg.
 43. The method of claim 42,wherein the therapeutically effective dose is about 3,000 mg.
 44. Themethod of claim 42, wherein the therapeutically effective dose is anamount from about 10 mg to about 1,000 mg.
 45. The method of claim 44,wherein the therapeutically effective dose is an amount from about 50 mgto about 500 mg.
 46. A method of treating a subject suffering fromneuropathic pain comprising administering to the subject 500 mg ofN-(2-n-propylpentanoyl)glycinamide six times per day so as to therebytreat the subject's neuropathic pain.
 47. A method of preventing pain ina subject predisposed to suffering from pain comprising periodicallyadministering to the subject a prophylactically effective dose of acompound having the following structure:

wherein R₁, R₂, R₃ and R₄ are independently the same or different andare hydrogen, a linear or branched C₁-C₆ alkyl group, an aralkyl group,or an aryl group, and n is an integer which is greater than or equal to0 and less than or equal to 3, so as to thereby prevent pain in thesubject.
 48. The method of claim 47, wherein one or more of R₁, R₂, R₃or R₄ is a linear chain C₁-C₆ alkyl group.
 49. The method of claim 47,wherein one or more of R₁, R₂, R₃ or R₄ is a branched chain C₁-C₆ alkylgroup.
 50. The method of claim 47, wherein one or more of R₁, R₂, R₃ orR₄ is a benzyl, alkylbenzyl, hydroxybenzyl, alkoxycarbonylbenzyl,aryloxycarbonylbenzyl, carboxybenzyl, nitrobenzyl, cyanobenzyl, orhalobenzyl group.
 51. The method of claim 47, wherein one or more of R₁,R₂, R₃ or R₄ is a phenyl, naphthyl, anthracenyl, pyridinyl, indolyl,furanyl, alkylphenyl, hydroxyphenyl, alkoxycarbonylphenyl,aryloxycarbonylphenyl, nitrophenyl, cyanophenyl, halophenyl group,mercaptophenyl, or aminophenyl group.
 52. The method of claim 47,wherein the pain is acute pain.
 53. The method of claim 47, wherein thepain is chronic pain.
 54. The method of claim 47, wherein the pain issomatogenic pain.
 55. The method of claim 54, wherein the somatogenicpain is neuropathic pain.
 56. The method of claim 47, wherein thesubject is a human being.
 57. The method of claim 47, wherein theadministration is oral, parenteral, intraperitoneal, intravenous,intramuscular, transdermal, subcutaneous, topical or rectaladministration.
 58. The method of claim 47, wherein the administrationis by inhalation, sublingual, nasal, buccal, pulmonary or vaginaladministration.
 59. The method of claim 47, wherein the periodicadministration is effected daily.
 60. The method of claim 47, whereinthe periodic administration is effected less than or equal to six timesa day.
 61. The method of claim 60, wherein the periodic administrationis effected six times a day.
 62. The method of claim 47, wherein theprophylactically effective dose is an amount from about 10 mg to about6,000 mg.
 63. The method of claim 62, wherein the prophylacticallyeffective dose is an amount from about 500 mg to about 4,000 mg.
 64. Themethod of claim 62, wherein the prophyla ctically effective dose is anamount from about 10 mg to about 3,000 mg.
 65. The method of claim 64,wherein the prophylactically effective dose is about 3,000 mg.
 66. Themethod of claim 64, wherein the prophylactically effective dose is anamount from about 10 mg to about 1,000 mg.
 67. The method of claim 66,wherein the prophylactically effective dose is an amount from about 50mg to about 500 m.
 68. The method of claim 47, wherein the compound thefollowing structure:


69. The method of claim 68, wherein the compound isN-(2-n-propylpentanoyl)glycinamide.
 70. The method of claim 69, whereinthe prophylactically effective dose is 3000 mg/day and the pain isneuropathic 5 pain.
 71. The method of claim 68, wherein the compound isN-2(-n-propylpent-2-enoyl)glycinamide.
 72. The method of claim 68,wherein one or more of R₁, R₂, R₃ or R₄ is a linear chain C₁-C₆ alkylgroup.
 73. The method of claim 68, wherein one or more of R₁, R₂, R₃ orR₄ is a branched chain C₁-C₆ alkyl group.
 74. The method of claim 68,wherein one or more of R₁, R₂, R₃ or R₄ is aralkyl group is a benzyl,alkylbenzyl, hydroxybenzyl, alkoxycarbonylbenzyl, aryloxycarbonylbenzyl,carboxybenzyl, nitrobenzyl, cyanobenzyl, or halobenzyl group.
 75. Themethod of claim 68, wherein one or more of R₁, R₂, R₃ or R₄ is a phenyl,naphthyl, anthracenyl, pyridinyl, indolyl, furanyl, alkylphenyl,hydroxyphenyl, alkoxycarbonylphenyl, aryloxycarbonylphenyl, nitrophenyl,cyanophenyl, halophenyl group, mercaptophenyl, or aminophenyl group. 76.The method of claim 68, wherein the pain is acute pain.
 77. The methodof claim 68, wherein the pain is chronic pain.
 78. The method of claim68, wherein the pain is somatogenic pain.
 79. The method of claim 78,wherein the somatogenic pain is neuropathic pain.
 80. The method ofclaim 68, wherein the subject is a human being.
 81. The method of claim68, wherein the administration oral, parenteral, intraperitoneal,intravenous, intramuscular, transdermal, subcutaneous, topical or rectaladministration.
 82. The method of claim 68, wherein the administrationis by inhalation, sublingual, nasal, buccal, pulmonary or vaginaladministration.
 83. The method of claim 68, wherein the periodicadministration is effected daily.
 84. The method of claim 68, whereinthe periodic administration is effected less than or equal to six timesa day.
 85. The method of claim 68, wherein the periodic administrationis effected six times a day.
 86. The method of claim 68, wherein theprophylactically effective dose is an amount from about 10 mg to about6,000 mg.
 87. The method of claim 86, wherein the prophylacticallyeffective dose is an amount from about 500 mg to about 4,000 mg.
 88. Themethod of claim 86, wherein the prophylactically effective dose is anamount from about 10 mg to about 3,000 mg.
 89. The method of claim 88,wherein the prophylactically effective dose is about 3,000 mg.
 90. Themethod of claim 88, wherein the prophylactically effective dose is anamount from about 10 mg to about 1,000 mg.
 91. The method of claim 90,wherein the prophylactically effective dose is an amount from about 50mg to about 500 mg.
 92. A method of preventing neuropathic pain in asubject predisposed to suffering from neuropathic pain comprisingadministering to the subject 500 mg ofN-(2-n-propylpentanoyl)glycinamide six times per day so as to therebyprevent the neuropathic pain in the subject.
 93. A method of treating asubject suffering from pain comprising periodically administering to thesubject a pharmaceutical composition comprising a therapeuticallyeffective dose a compound having the following structure:

wherein R₁, R₂, R₃ and R₄ are independently the same or different andare hydrogen, a linear or branched C₁-C₆ alkyl group, an aralkyl group,or an aryl group, and n is an integer which is greater than or equal to0 and less than or equal to 3, and a pharmaceutically acceptablecarrier, so as to thereby treat the subject's pain.
 94. A method ofpreventing pain in a subject predisposed to suffering from paincomprising periodically administering to the subject a compositioncomprising a prophylactically effective dose of a compound having thefollowing structure:

wherein R₁, R₂, R₃ and R₄ are independently the same or different andare hydrogen, a linear or branched C₁-C₆ alkyl group, an aralkyl group,or an aryl group, and n is an integer which is greater than or equal to0 and less than or equal to 3, and a pharmaceutically acceptablecarrier, so as to thereby prevent pain in the subject.
 95. A method oftreating a subject suffering from a headache disorder comprisingperiodically administering to the subject a therapeutically effectivedose of a compound having the following structure:

wherein R₁, R₂, R₃ and R₄ are independently the same or different andare hydrogen, a linear or branched C₁-C₆ alkyl group, an aralkyl group,or an aryl group, and n is an integer which is greater than or equal to0 and less than or equal to 3, so as to thereby treat the headachedisorder.
 96. A method of preventing a headache disorder in a subjectpredisposed to suffering from a headache disorder comprisingperiodically administering to the subject a prophylactically effectivedose of a compound having the following structure:

wherein R₁, R₂, R₃ and R₄ are independently the same or different andare hydrogen, a linear or branched C₁-C₆ alkyl group, an aralkyl group,or an aryl group, and n is an integer which is greater than or equal to0 and less than or equal to 3, so as to thereby prevent the headachedisorder in the subject.